The present invention is directed to a novel biologically active agent useful for the treatment of hypertension, congestive heart failure, atrial fibrillation and idiopathic edema in mammals.
Congestive heart disease is characterized by an incomplete emptying of blood from the heart during ventricular contraction, which leads to an enlargement of the heart. When treated with drugs (cardiac glycosides), there is a reduction of heart rate, a more complete filling of the ventricles, and the size of the heart decreases and begins to return to normal.
Atrial fibrillation is a condition in which the atria contract much more often than the ventricles, causing the lower heart chambers to be bombarded by impulses. The ventricles respond by weakly and inefficiently contracting. The drugs (cardiac glycosides) used to treat atrial fibrillation depress this conduction, slow the rate of the ventricular contraction and help re-establish a synchronous and effective heartbeat.
Digitalis, digoxin, ouabain and related steroid glycosides are a class of compounds known as cardiotoxic agents which enhance the force of contraction of the heart. One class of cardiotoxic agents, the cardiac glycosides (such as digitalis, digoxin and ouabain) are characterized by a basic cyclopentanoperhydrohenanthrene nucleus to which is attached an unsaturated lactone ring at C17. This structure, termed an aglycone, is combined with one to four molecules of sugar. The pharmacological action resides in the aglycone, but the sugar moieties affect solubilization properties and the potency of the resulting glycoside.
The most important therapeutic uses of cardiac glycoside drugs is the treatment of congestive heart failure and atrial fibrillation. When digitalis is used to treat congestive heart failure, the beneficial effects produced have been attributed to the drug's positive inotropic (influencing muscular contractility) effect. The greater force of contraction resulting from administration of the drug increases the release of blood from the heart, increasing cardiac output and improving systemic circulation.
One of the drawbacks of digoxin and its congeners is their low therapeutic index. There is a narrow window of concentrations in which the drugs are effective for the treatment of congestive heart failure or atrial fibrillation. In addition, there are numerous adverse side effects resulting from therapy with digoxin and related cardiac glycosides. These have been extensively reviewed by T. W. Smith et al. in Prog. Cardiovas. Dis. 26:21-56, 1984. Side effects of digoxin therapy include impotence, weakness, and depression. A further drawback is that some patients do not respond to digoxin treatment. Furthermore, digoxin and digitalis are only effective to depress blood pressure in patients that have previously suffered congestive heart failure and are ineffective in normal hypertensive patients. Ouabain is very rapid--acting has a half-life of 21 hours and is rapidly excreted by the kidneys. As a result, its use is limited to emergency treatment.
Hypertension is a common condition and is characterized by elevations of atrial pressure which could result in secondary organ damage and a reduced lifespan. The condition is currently treated using four general classes of drugs: diuretics, anti-adrenergic agents, vasodilators and angiotension blockers (Harrison's Principles of Internal Medicine, K. J. Issel Bacher et al. eds, pp. 1172-1176, McGraw-Hill, New York 1980). Each of the above produce side effects and their use is limited. Cardiac glycosides (used to treat congestive heart disease) are essentially ineffective in treating hypertension.
Idiopathic edema is characterized by periodic episodes of edema or water retention. The current treatments available are non-specific and include administration of diuretics, beta adrenergic blockers such as propanolol, bed rest, and reduction in dietary salt intake.
A new active biological agent has now been unexpectedly derived from human breast cyst fluid. In particular, Type 1 human female breast cyst fluid has been found to contain a biologically active agent which can be administered to mammals to lower their blood pressure. The new biological agent cross-reacts with specific antibodies to digoxin, a well known cardiac glycoside. Surprisingly, it was also found that the new biologically active agent stimulated the activity of the Na.sup.+ K.sup.+ -ATPase enzyme, unlike digoxin and related cardiac glycosides. The action of this enzyme provides a diuretic effect which may account for the observed hypotensive effect.
A principal object of the present invention is to provide a new biologically active agent.
A further object of the present invention is to provide a new biologically active agent, derived from human female breast cyst fluid, that has the property of lowering mammalian blood pressure and which can also be used to treat congestive heart failure, atrial fibrillation and idiopathic edema in mammals.
Another object of the present invention is to provide a method of treating hypertension in a mammal by administration of a biologically active agent derived from human female breast cyst fluid.
A still further object of the present invention is to provide a novel pharmaceutical formulation for treating hypertension in mammals comprising a biologically active agent derived from human female breast cyst fluid and pharmaceutically acceptable salts and/or carriers.
These and other objects of the present invention will be apparent to one of ordinary skill in the art in light of the present description, accompanying claims and appended drawings.